CLDN18 (Claudin 18)

Patients were randomized 1:1 to receive zolbetuximab plus chemotherapy or placebo plus chemotherapy (mFOLFOX6 [modified folinic acid, 5-fluorouracil, and oxaliplatin] or CAPOX [capecitabine and oxaliplatin]). Zolbetuximab plus chemotherapy demonstrated favorable PFS and OS versus placebo plus chemotherapy in the Korean subgroup, with numerically greater efficacy compared with the overall pooled population. This may be potentially attributable to low rates of zolbetuximab discontinuation and toxicity management.

Finally, we identify current limitations in the field, including inconsistent CLDN18.2 testing criteria, and outline prioritized future directions to optimize integration of CLDN18.2-directed therapies across gastrointestinal cancers. By looking beyond zolbetuximab and incorporating cross-platform comparison, immuno-oncology considerations, and multi-tumor context, this review provides a broad and forward-looking framework to guide clinical application and next-generation research in CLDN18.2-targeted therapy.

This review provides a comprehensive overview of the evolving therapeutic landscape of GEC. It emphasizes the growing role of precision medicine and the integration of emerging clinical data into practice.

In addition to the quality guideline-compliant technical performance of the tests, the biological heterogeneity of many of these biomarkers is also a diagnostic and clinical challenge. The current article provides an overview of current biomarker testing in the context of current treatment options for cancer of the upper gastrointestinal tract.

pDuFLOT and pSOX are potential regimens among senior patients with resectable gastric cancer. At this moment, pDuFLOT may be globally used while pSOX should better be applied among East Asian countries. CadCAPOX, SuCAPOX, PemCAPOX and NiCAPOX are considered as potential first-line regimens among HER2-negative senior patients. CadCAPOX and SuCAPOX are probably more fit for East Asian patients currently, while NiCAPOX may be better applied among Western countries and PemCAPOX has the potential of worldwide application. SuCAPOX is a potential regimen among HER2-negative/PD-L1-positive senior patients, while PemCAPOX may also be considered. Currently, standard CAPOX or FOLFOX regimen may still be available for HER2-negative senior patients with CLDN18.2, FGFR2b or MET positivity. Meanwhile, among HER2-positive senior patients, TraCAPOX is still considered to be available. Regarding first-line maintenance treatments, RamP is a potential regimen among HER2-negative or non-specific senior patients, especially those from Western countries. As second-line regimens, FruP and RamP may be potentially available among East Asian and worldwide HER2-negative senior patients respectively, while T-DXd has the potential of global application among HER2-positive counterparts. Concerning third-line or subsequent regimens, T-DXd is potentially available among HER2-positive senior patients, especially from East Asian countries. Among HER2-negative or non-specific patients, RamIRI is a potential regimen, especially among East Asian patients, while nivolumab and regorafenib may still be available at this moment. Meanwhile, nivolumab and other parallel regimens already recommended by guidelines are still potentially available among HER2-negative/CLDN18.2-positive senior patients. As the first network meta-analysis on this topic, our conclusions may not only provide potential supplements for current guidelines, but also reveal the necessity and directions for future clinical and mechanism researches, especially because of the underpowered subgroup data and exploratory nature of regional applicability.

This study presents a case of Claudin18.2-positive advanced gastric adenocarcinoma with peritoneal metastasis treated with a multimodal regimen: HIPEC, systemic CapeOx chemotherapy, and Claudin18.2-targeted therapy (ASKB589)...At 893 days post-diagnosis, the patient remains disease-free (PFS/DFS: 893/573 days) on adjuvant capecitabine...However, the absence of cytoreductive surgery and single-case limitations necessitate validation through randomized trials. Future research should prioritize biomarker-driven HIPEC protocols (e.g., nanoparticle-enhanced Claudin18.2-targeted delivery) and dynamic monitoring of Claudin18.2 expression during therapy.

Growing evidence identifies Claudin18.2 as both a biomarker of aggressive disease and an attractive therapeutic target. Monoclonal antibodies and antibody-drug conjugate directed against Claudin18.2 are currently being evaluated in clinical trials, showing encouraging antitumor activity.

The study indicates that the use of antibiotics for infection reduces the efficacy outcomes of CLDN18.2-specific CAR-T cell therapy for advanced GC, while other concomitant medications do not affect the outcomes. Further research is needed to clarify the optimal administration of these medications and the underlying mechanisms of the gut microbiome in impacting CAR-T treatment response.

CLDN18.2 was not significantly associated with PD-L1 or HER2 status regardless of histological subtype (P > 0.05). This study characterized the histological profile of CLDN18.2-positive G/GEJ and broadened our understanding of subgroups likely to benefit from CLDN18.2-targeted therapy.

GAC may demonstrate distinctive morphology-dependent Claudin 18.2 expression, suggesting potential implications for targeted therapy selection and molecular subtyping. The morphological heterogeneity and aggressive clinical behavior underscore the importance of accurate diagnosis through comprehensive integrated assessment.

Zolbetuximab is associated with high rates of nausea and vomiting during the initial infusion, whereas ICIs are associated with risk of later-onset immune-related toxicities that can be fatal in rare cases. In considering the available evidence, our opinion is that zolbetuximab is a reasonable option for initial targeted treatment in HER2-/CLDN18.2-positive advanced G/GEJ when PD-L1 CPS score is <10 based on the reliability of biomarker testing, comparable OS, and avoidance of potentially irreversible ICI-induced immune toxicity.